The following was released late Friday and is being retransmitted:
WHITEHOUSE STATION, N.J. -- Merck & Co., Inc., announced Friday that the U.S. Food and Drug Administration (FDA) granted ISENTRESSTM (raltegravir) tablets accelerated approval for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents.
This indication is based on analyses of plasma HIV-1 RNA levels up through 24 weeks in two controlled studies of ISENTRESS [pronounced i-sen-tris]. These studies were conducted in clinically advanced, three-class antiretroviral [nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs)] treatment-experienced adults. The use of other active agents with ISENTRESS is associated with a greater likelihood of treatment response. The safety and efficacy of ISENTRESS have not been established in treatment-naïve adult patients or pediatric patients. There are no study results demonstrating the effect of ISENTRESS on clinical progression of HIV-1 infection. Longer term data will be required before the FDA can consider traditional approval for ISENTRESS.
ISENTRESS is the first medicine to be approved in a new class of antiretroviral drugs called integrase inhibitors. ISENTRESS works by inhibiting the insertion of HIV DNA into human DNA by the integrase enzyme. Inhibiting integrase from performing this essential function limits the ability of the virus to replicate and infect new cells. There are drugs in use that inhibit two other enzymes critical to the HIV replication process – protease and reverse transcriptase – but ISENTRESS is the only drug approved that inhibits the integrase enzyme.
The FDA’s decision was based on a 24-week analysis of clinical trials in which ISENTRESS in combination with optimized background therapy (OBT) in treatment-experienced patients, provided significant reductions in HIV RNA viral load and increases in CD4 cell counts.
“The development of ISENTRESS is a significant milestone in the history of HIV/AIDS therapy because we now have a drug that's potent against another key enzyme essential for viral replication,” said Joseph J. Eron Jr., M.D., professor of medicine, Division of Infectious Diseases, UNC Chapel Hill School of Medicine. "It's important for physicians to know that ISENTRESS should always be used in combination with other active agents."
Data from two ongoing Phase III multi-center, double-blind, randomized, placebo-controlled studies (BENCHMRK-1 and BENCHMRK-2) in 699 treatment-experienced adult patients with documented resistance to at least one drug in each of three classes (NRTIs, NNRTIs and PIs) of antiretroviral therapies showed that ISENTRESS 400 mg dosed twice daily in combination with OBT was significantly more effective at both reducing levels of HIV viral RNA and increasing CD4 cell counts in these patients living with HIV, when compared to a regimen of placebo plus OBT.
Pooled analyses from the two Phase III studies showed that after 24 weeks of therapy, 75.5 percent of patients (216 out of 286) receiving ISENTRESS in combination with OBT achieved HIV viral RNA load reduction to below 400 copies/mL compared to 39.3 percent of patients (59 out of 150) receiving placebo plus OBT. In addition, after 24 weeks of therapy, 62.6 percent of patients (179 out of 286) receiving ISENTRESS plus OBT achieved viral load reduction to below 50 copies/mL compared to 33.3 percent of patients (50 out of 150) receiving placebo plus OBT. After 24 weeks of therapy, increases in CD4 cell counts from baseline were 89 and 35 cells/mm3 for patients receiving ISENTRESS plus OBT and for those receiving placebo plus OBT, respectively.
“ISENTRESS is the first drug in a new class of antiretroviral therapies that when used in combination with other effective antiretroviral agents, offers a new opportunity for individuals whose HIV infection is no longer adequately controlled and whose virus is resistant to multiple agents," said Peter S. Kim, Ph.D., president, Merck Research Laboratories. "This approval builds on our long standing commitment to research in HIV/AIDS, with the goal of making truly differentiated therapies available to patients in need."
Important safety information about ISENTRESS
ISENTRESS does not cure HIV or AIDS and does not prevent passing HIV to others. Healthcare providers should know that immune reconstitution syndrome has been reported in patients treated with antiretroviral therapy, which may necessitate further evaluation and treatment.
The most commonly reported adverse experiences of any severity (mild, moderate or severe) regardless of drug relationship were diarrhea (16.6 percent vs. 19.5 percent), nausea (9.9 percent vs. 14.2 percent), headache (9.7 percent vs. 11.7 percent) and fever (4.9 percent vs. 10.3 percent) for ISENTRESS plus OBT and placebo plus OBT, respectively.
Creatine kinase elevations were observed in subjects who received ISENTRESS. Myopathy and rhabdomyolysis have been reported; however, the relationship of ISENTRESS to these events is not known. ISENTRESS should be used with caution in patients at increased risk of myopathy or rhabdomyolysis, such as patients receiving concomitant medication known to cause these conditions.
Safety and tolerability profile of ISENTRESS
Results from pooled safety analyses from three separate studies in treatment-experienced patients taking 400 mg of ISENTRESS dosed twice daily plus OBT or placebo plus OBT showed that after 24 weeks of therapy the rates of discontinuation of therapy due to adverse experiences were 2.0 percent in patients receiving ISENTRESS plus OBT and 1.4 percent in patients receiving placebo plus OBT. In addition, drug-related clinical adverse events of moderate to severe intensity occurring in greater than or equal to 2.0 percent of patients were diarrhea (3.7 percent vs. 4.6 percent), nausea (2.2 percent vs. 3.2 percent) and headache (2.4 percent vs. 1.4 percent) for ISENTRESS plus OBT and placebo plus OBT, respectively.
Drug interactions
Based on the results of drug interaction studies and the clinical trials data, no dose adjustment of ISENTRESS is required when coadministered with other antiretroviral agents. Also, preclinical studies show that ISENTRESS is not metabolized by cytochrome P450 enzymes. Caution should be used when coadministering ISENTRESS with strong inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1 (e.g., rifampin) due to reduced plasma concentrations of ISENTRESS.
About ISENTRESS
ISENTRESS is a single 400 mg tablet taken twice daily without regard to food. ISENTRESS does not require boosting with ritonavir.
Merck has worked closely with the HIV community regarding the price of ISENTRESS. The wholesale acquisition cost (WAC) of ISENTRESS will be $27 per day, comparable to the price of several available ritonavir-boosted protease inhibitors.
"ISENTRESS is the first drug in a new class of medications and the Fair Pricing Coalition is pleased to report that Merck has acted responsibly in its pricing of the drug. While we still believe that lower prices are always possible, Merck has avoided the temptation to set ever higher prices for each new HIV drug,” said Martin Delaney of the Fair Pricing Coalition (FPC) and Project Inform. The FPC is a nationwide network of activists and organizations concerned with drug pricing that works with pharmaceutical companies to set responsible prices.
To help patients in the United States who cannot afford treatment with ISENTRESS, the SUPPORT™ program is available. The SUPPORT program is a patient assistance program to help patients who have been prescribed ISENTRESS by providing personalized support and patient advocacy regarding individual reimbursement issues. In addition, Merck also participates in the Partnership for Prescription Assistance program, a single point of access to more than 475 public and private patient assistance programs. ISENTRESS will be available in pharmacies in approximately two weeks. For more information on ISENTRESS, visit www.isentress.com.
Expanded access program
ISENTRESS is currently available worldwide to qualified patients through an expanded access clinical research program, EARMRK. This global program provides early access to ISENTRESS for patients failing current therapy whose HIV is resistant to drugs in three existing classes (NRTIs, NNRTIs, PIs) of antiretroviral medications. Information about the program can be found at www.benchmrk.com.
Merck HIV research
Merck is committed to developing innovative therapies that offer advances in the treatment of infectious diseases – including HIV. Merck's efforts to develop investigational treatments for HIV/AIDS have been under way for more than 20 years and continue today. Merck began its HIV integrase inhibitor research in 1993 and was the first to demonstrate inhibition of HIV integrase in vitro and in vivo.
Prevalence of HIV/AIDS
In 2006, over one million Americans were living with HIV/AIDS and it is estimated that approximately 40,000 new cases of HIV/AIDS are diagnosed each year in the United States. Worldwide, an estimated 40 million people are infected with HIV/AIDS, and more than four million new infections occurred in 2006.
“As the AIDS crisis continues, new drugs like ISENTRESS are needed, which target the virus in unique ways," said Ben Cheng, deputy director, Forum for Collaborative HIV Research. "The HIV Advocacy Community is really excited and encouraged by this new treatment."
About Merck
Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The Company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit www.merck.com.
Forward-looking statement
This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management’s current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the risk factors and cautionary statements in Item 1A of Merck's Form 10-K for the year ended Dec. 31, 2006, and in its periodic reports on Form 10-Q and Form 8-K, which the company incorporates by reference.
ISENTRESS™ is a trademark of Merck & Co., Inc.
SUPPORT™ is a trademark of Merck & Co., Inc.
Full prescribing information and patient product information for ISENTRESS™ is attached.
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
ISENTRESS safely and effectively. See full prescribing information for
ISENTRESS.
ISENTRESS (raltegravir) Tablets
Initial U.S. Approval: 2007
INDICATIONS AND USAGE
ISENTRESS(TM) is a human immunodeficiency virus integrase strand
transfer inhibitor (HIV-1 INSTI) indicated:
-- In combination with other antiretroviral agents for the
treatment of HIV-1 infection in treatment-experienced adult
patients who have evidence of viral replication and HIV-1
strains resistant to multiple antiretroviral agents (1).
The safety and efficacy of ISENTRESS have not been established in
treatment-naive adult patients or pediatric patients (1).
DOSAGE AND ADMINISTRATION
-- 400 mg administered orally, twice daily with or without food
(2.1).
DOSAGE FORMS AND STRENGTHS
Tablets: 400 mg (3).
CONTRAINDICATIONS
None
WARNINGS AND PRECAUTIONS
Monitor for Immune Reconstitution Syndrome (5.1)
Drug Interactions
-- Caution should be used when coadministering ISENTRESS with
strong inducers of uridine diphosphate glucuronosyltransferase
(UGT) 1A1 (e.g., rifampin) due to reduced plasma
concentrations of raltegravir (5.2).
ADVERSE REACTIONS
-- The most common adverse reactions (>10%) of all intensities,
reported in subjects in either the ISENTRESS or the placebo
treatment group, regardless of causality were: nausea,
headache, diarrhea and pyrexia (6.1).
-- Creatine kinase elevations were observed in subjects who
received ISENTRESS. Myopathy and rhabdomyolysis have been
reported; however, the relationship of ISENTRESS to these
events is not known. Use with caution in patients at increased
risk of myopathy or rhabdomyolysis, such as patients receiving
concomitant medications known to cause these conditions (6.1).
To report SUSPECTED ADVERSE REACTIONS, contact Merck & Co., Inc.
at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
USE IN SPECIFIC POPULATIONS
Pregnancy:
-- ISENTRESS should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
Physicians are encouraged to register pregnant women exposed
to ISENTRESS by calling 1-800-258-4263 so that Merck can
monitor maternal and fetal outcomes (8.1).
Nursing Mothers:
-- Breast-feeding is not recommended while taking ISENTRESS
(8.3).
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient
labeling.
Revised: 10/2007
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Dosing Information
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Immune Reconstitution Syndrome
5.2 Drug Interactions
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
7 DRUG INTERACTIONS
7.1 Effect of Raltegravir on the Pharmacokinetics of Other Agents
7.2 Effect of Other Agents on the Pharmacokinetics of Raltegravir
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Use in Patients with Hepatic Impairment
8.7 Use in Patients with Renal Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
12.4 Microbiology
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the Full Prescribing
Information are not listed.
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
ISENTRESS(1) in combination with other antiretroviral agents is
indicated for the treatment of HIV-1 infection in
treatment-experienced adult patients who have evidence of viral
replication and HIV-1 strains resistant to multiple antiretroviral
agents.
This indication is based on analyses of plasma HIV-1 RNA levels up
through 24 weeks in two controlled studies of ISENTRESS. These studies
were conducted in clinically advanced, 3-class antiretroviral (NNRTI,
NRTI, PI) treatment-experienced adults.
The use of other active agents with ISENTRESS is associated with a
greater likelihood of treatment response (see Clinical Studies (14)).
The safety and efficacy of ISENTRESS have not been established in
treatment-naive adult patients or pediatric patients.
There are no study results demonstrating the effect of ISENTRESS
on clinical progression of HIV-1 infection.
2 DOSAGE AND ADMINISTRATION
2.1 Dosing Information
For the treatment of patients with HIV-1 infection, the dosage of
ISENTRESS is 400 mg administered orally, twice daily with or without
food.
3 DOSAGE FORMS AND STRENGTHS
400 mg pink, oval-shaped, film-coated tablets with "227" on one
side.
4 CONTRAINDICATIONS
None
5 WARNINGS AND PRECAUTIONS
5.1 Immune Reconstitution Syndrome
During the initial phase of treatment, patients responding to
antiretroviral therapy may develop an inflammatory response to
indolent or residual opportunistic infections (such as Mycobacterium
avium complex, cytomegalovirus, Pneumocystis jiroveci pneumonia,
Mycobacterium tuberculosis, or reactivation of varicella zoster
virus), which may necessitate further evaluation and treatment.
5.2 Drug Interactions
Caution should be used when coadministering ISENTRESS with strong
inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1
(e.g., rifampin) due to reduced plasma concentrations of raltegravir
(see Drug Interactions (7)).
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying
conditions, adverse reaction rates observed in the clinical trials of
a drug cannot be directly compared to rates in the clinical trials of
another drug and may not reflect the rates observed in practice.
Treatment-Experienced Studies
The safety assessment of ISENTRESS in treatment-experienced
subjects is based on the pooled safety data from the randomized,
double-blind, placebo-controlled trials, BENCHMRK 1 and BENCHMRK 2
(Protocols 018 and 019), and the randomized, double-blind,
placebo-controlled, dose-ranging trial (Protocol 005) in
antiretroviral treatment-experienced HIV-1 infected adult subjects
reported using the recommended dose of ISENTRESS 400 mg twice daily in
combination with optimized background therapy (OBT) in 507 subjects,
in comparison to 282 subjects taking placebo in combination with OBT.
During double-blind treatment, the total follow-up was 332.2
patient-years in the ISENTRESS 400 mg twice daily group and 150.2
patient-years in the placebo group.
The most commonly (>10%) reported adverse reactions, of all
intensities, regardless of causality in subjects treated with
ISENTRESS and OBT versus placebo and OBT are presented in Table 1.
Table 1: Percentage of Subjects with the Most Commonly Reported
(>10%) Adverse Reactions of All Intensities* and Regardless of
Causality Occurring in
Treatment-Experienced Adult Subjects
Randomized Studies
P005, P018 and P019
----------------------
System Organ Class, Adverse Reactions ISENTRESS Placebo
400 mg + OBT
twice daily (n=282)+
+ OBT %
(n=507)+
%
----------------------------------------------- ------------ --------
Gastrointestinal Disorders
----------------------------------------------------------------------
Diarrhea 16.6 19.5
----------------------------------------------- ------------ --------
Nausea 9.9 14.2
----------------------------------------------- ------------ --------
Nervous System Disorders
----------------------------------------------------------------------
Headache 9.7 11.7
----------------------------------------------- ------------ --------
General Disorders and Administration Site Conditions
----------------------------------------------------------------------
Pyrexia 4.9 10.3
----------------------------------------------- ------------ --------
*Intensities are defined as follows: Mild (awareness of sign or
symptom, but easily tolerated); Moderate (discomfort enough to cause
interference with usual activity); Severe (incapacitating with
inability to work or do usual activity).
+n=total number of subjects per treatment group.
The clinical adverse reactions listed below were considered by
investigators to be of moderate to severe intensity and causally
related to any drug in the combination regimen (ISENTRESS/placebo
alone or in combination with OBT, or OBT alone):
Common Adverse Reactions
Drug-related clinical adverse reactions of moderate to severe
intensity occurring in =>2% of subjects treated with ISENTRESS + OBT
are presented in Table 2.
Table 2: Percentage of Subjects with Drug-Related* Adverse
Reactions of Moderate to Severe Intensity+ Occurring in =>2% of
Treatment-Experienced Adult Subjects
Randomized Studies P005,
P018 and P019
--------------------------
System Organ Class, Adverse Reactions ISENTRESS 400 mg Placebo
Twice Daily + OBT
+ OBT (n =
(n = 507)++ 282)++
% %
----------------------------------------- ---------------- -------
Gastrointestinal Disorders
----------------------------------------------------------------------
Diarrhea 3.7 4.6
----------------------------------------- ---------------- -------
Nausea 2.2 3.2
----------------------------------------- ---------------- -------
Nervous System Disorders
----------------------------------------------------------------------
Headache 2.4 1.4
----------------------------------------- ---------------- -------
*Includes adverse reactions at least possibly, probably, or very
likely related to the drug.
+Intensities are defined as follows: Moderate (discomfort enough to
cause interference with usual activity); Severe (incapacitating with
inability to work or do usual activity).
++n=total number of subjects per treatment group.
Less Common Adverse Reactions
Drug-related adverse reactions occurring in at least 1% but less
than 2% of treatment-experienced subjects (n=507) receiving ISENTRESS
+ OBT and of moderate (discomfort enough to cause interference with
usual activity) to severe (incapacitating with inability to work or do
usual activity) intensity are listed below by system organ class:
Gastrointestinal Disorders: abdominal pain, vomiting
General Disorders and Administration Site Conditions: asthenia,
fatigue
Nervous System Disorders: dizziness
Skin and Subcutaneous Tissue Disorders: lipodystrophy acquired
Discontinuations
In the pooled analyses for studies P005, P018 and P019, the rates
of discontinuation of therapy due to adverse reactions were 2.0% in
subjects receiving ISENTRESS + OBT and 1.4% in subjects receiving
placebo + OBT.
Serious Events
Drug Related
The following serious drug-related reactions were reported in the
clinical studies, P005, P018 and P019: hypersensitivity
(hypersensitivity was seen in 2 subjects with ISENTRESS; therapy was
interrupted and upon rechallenge the subjects were able to resume
drug), anemia, neutropenia, myocardial infarction, gastritis,
hepatitis, herpes simplex, toxic nephropathy, renal failure, chronic
renal failure and renal tubular necrosis.
Regardless of Drug Relationship
Cancers were reported in treatment-experienced subjects who
initiated ISENTRESS with OBT; several were recurrent. The types and
rates of specific cancers were those expected in a highly
immunodeficient population (many had CD4+ cell counts below
50 cells/mm(3) and most had prior AIDS diagnoses). The cancers
included Kaposi's sarcoma, lymphoma, squamous cell carcinoma,
hepatocellular carcinoma and anal cancer. Most subjects had other risk
factors for cancer including tobacco use, papillomavirus and active
hepatitis B virus infection. It is unknown if these cancer diagnoses
were related to ISENTRESS use.
Grade 2-4 creatine kinase laboratory abnormalities were observed
in subjects treated with ISENTRESS (see Table 3). Myopathy and
rhabdomyolysis have been reported; however, the relationship of
ISENTRESS to these events is not known. Use with caution in patients
at increased risk of myopathy or rhabdomyolysis, such as patients
receiving concomitant medications known to cause these conditions.
Patients with Co-existing Conditions
Patients Co-infected with Hepatitis B and/or Hepatitis C Virus
In the clinical studies, P018 and P019, subjects with chronic (but
not acute) active hepatitis B and/or hepatitis C virus co-infection (N
= 113/699 or 16.2%) were permitted to enroll provided that baseline
liver function tests did not exceed 5 times the upper limit of normal
(ULN). The rates of AST and ALT abnormalities were somewhat higher in
the subgroup of subjects with hepatitis B and/or hepatitis C virus
co-infection for both treatment groups. In general the safety profile
of ISENTRESS in subjects with hepatitis B and/or hepatitis C virus
co-infection was similar to subjects without hepatitis B and/or
hepatitis C virus co-infection. Grade 2 or higher laboratory
abnormalities that represent a worsening from baseline of AST, ALT or
total bilirubin occurred in 26%, 27% and 12%, respectively, of
raltegravir-treated coinfected subjects as compared to 9%, 8% and 7%
of all other raltegravir-treated subjects.
Laboratory Abnormalities
The percentages of adult subjects treated with ISENTRESS 400 mg
twice daily in P005, P018 and P019 with selected Grades 2 to 4
laboratory abnormalities that represent a worsening from baseline are
presented in Table 3.
Table 3: Selected Grade 2 to 4 Laboratory Abnormalities Reported
in Treatment-Experienced Subjects
Randomized
Studies P005,
P018 and P019
ISENTRESS Placebo
400 mg +
Laboratory Parameter Preferred Term Limit Twice OBT
(Unit) Daily + (N =
OBT 282)
(N = 507)
---------------------------------------- --------------------- -------
Hematology
---------------------------------------- -----------------------------
Absolute neutrophil count (103/
(mu)L)
Grade 2 0.75 - 0.999 3.7%7.4%
Grade 3 0.50 - 0.749 2.4%2.5%
Grade 4 0.50 1.0%1.1%
---------------------------------------- -----------------------------
Hemoglobin (gm/dL)
Grade 2 7.5 - 8.4 1.0%2.8%
Grade 3 6.5 - 7.4 1.0%0.4%
Grade 4 6.5 0.0%0.0%
---------------------------------------- -----------------------------
Platelet count (103/(mu)L)
Grade 2 50 - 99.999 3.7%5.7%
Grade 3 25 - 49.999 0.4%0.4%
Grade 4 25 0.8%0.4%
---------------------------------------- -----------------------------
Blood chemistry
---------------------------------------- -----------------------------
Fasting (non-random) serum glucose test
(mg/dL)
Grade 2 126 - 250 9.3%6.8%
Grade 3 251 - 500 1.4%1.4%
Grade 4 >500 0.0%0.0%
---------------------------------------- -----------------------------
Total serum bilirubin
Grade 2 1.6 - 2.5 x
ULN 5.3%6.7%
Grade 3 2.6 - 5.0 x
ULN 3.2%2.5%
Grade 4 >5.0 x ULN 0.8%0.0%
---------------------------------------- -----------------------------
Serum aspartate aminotransferase
Grade 2 2.6 - 5.0 x
ULN 9.1%5.7%
Grade 3 5.1 - 10.0 x
ULN 2.2%2.1%
Grade 4 >10.0 x ULN 0.4%0.7%
---------------------------------------- -----------------------------
Serum alanine aminotransferase
Grade 2 2.6 - 5.0 x
ULN 6.9%7.8%
Grade 3 5.1 - 10.0 x
ULN 3.0%1.4%
Grade 4 >10.0 x ULN 0.6%1.1%
---------------------------------------- -----------------------------
Serum alkaline phosphatase
Grade 2 2.6 - 5.0 x
ULN 2.0%0.4%
Grade 3 5.1 - 10.0 x
ULN 0.4%1.1%
Grade 4 >10.0 x ULN 0.4%0.4%
---------------------------------------- -----------------------------
Serum pancreatic amylase test
Grade 2 1.6 - 2.0 x
ULN 1.4%0.7%
Grade 3 2.1 - 5.0 x
ULN 3.6%2.1%
Grade 4 >5.0 x ULN 0.2%0.0%
---------------------------------------- -----------------------------
Serum lipase test
Grade 2 1.6 - 3.0 x
ULN 3.4%1.8%
Grade 3 3.1 - 5.0 x
ULN 0.6%0.4%
Grade 4 >5.0 x ULN 0.2%0.0%
---------------------------------------- -----------------------------
Serum creatine kinase
Grade 2 6.0 - 9.9 x
ULN 2.2%1.4%
Grade 3 10.0 - 19.9
x ULN 2.4%1.8%
Grade 4 =>20.0 x ULN 2.2%0.7%
---------------------------------------- -----------------------------
ULN = Upper limit of normal range
7 DRUG INTERACTIONS
7.1 Effect of Raltegravir on the Pharmacokinetics of Other Agents
Raltegravir does not inhibit (IC50>100 uM) CYP1A2, CYP2B6, CYP2C8,
CYP2C9, CYP2C19, CYP2D6 or CYP3A in vitro. Moreover, in vitro,
raltegravir did not induce CYP3A4. A midazolam drug interaction study
confirmed the low propensity of raltegravir to alter the
pharmacokinetics of agents metabolized by CYP3A4 in vivo by
demonstrating a lack of effect of raltegravir on the pharmacokinetics
of midazolam, a sensitive CYP3A4 substrate. Similarly, raltegravir is
not an inhibitor (IC50>50 uM) of the UDP-glucuronosyltransferases
(UGT) tested (UGT1A1, UGT2B7), and raltegravir does not inhibit
P-glycoprotein-mediated transport. Based on these data, ISENTRESS is
not expected to affect the pharmacokinetics of drugs that are
substrates of these enzymes or P-glycoprotein (e.g., protease
inhibitors, NNRTIs, methadone, opioid analgesics, statins, azole
antifungals, proton pump inhibitors, oral contraceptives, and
anti-erectile dysfunction agents).
In drug interaction studies, raltegravir did not have a clinically
meaningful effect on the pharmacokinetics of the following:
lamivudine, tenofovir.
7.2 Effect of Other Agents on the Pharmacokinetics of Raltegravir
Raltegravir is not a substrate of cytochrome P450 (CYP) enzymes.
Based on in vivo and in vitro studies, raltegravir is eliminated
mainly by metabolism via a UGT1A1-mediated glucuronidation pathway.
Rifampin, a strong inducer of UGT1A1, reduces plasma
concentrations of ISENTRESS. Therefore, caution should be used when
coadministering ISENTRESS with rifampin or other strong inducers of
UGT1A1 (see Warnings and Precautions (5.2)). The impact of other
inducers of drug metabolizing enzymes, such as phenytoin and
phenobarbital, on UGT1A1 is unknown. Other less strong inducers (e.g.,
efavirenz, nevirapine, rifabutin, St. John's wort) may be used with
the recommended dose of ISENTRESS.
Similar to rifampin, tipranavir/ritonavir reduces plasma
concentrations of ISENTRESS. However, approximately 100 subjects
received raltegravir in combination with tipranavir/ritonavir in
Protocols 018 and 019. Comparable efficacy was observed in this
subgroup relative to subjects not receiving tipranavir/ritonavir.
Based on these data, tipranavir/ritonavir may be coadministered with
ISENTRESS without dose adjustment of ISENTRESS.
Atazanavir, a strong inhibitor of UGT1A1, and atazanavir/ritonavir
increase plasma concentrations of raltegravir. However, concomitant
use of ISENTRESS and atazanavir/ritonavir did not result in a unique
safety signal in Protocol 005 and Protocols 018 and 019. Based on
these data, atazanavir/ritonavir may be coadministered with ISENTRESS
without dose adjustment of ISENTRESS.
Coadministration of ISENTRESS with other drugs that inhibit UGT1A1
may increase plasma levels of raltegravir.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C
ISENTRESS should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus. There are no
adequate and well-controlled studies in pregnant women. In addition,
there have been no pharmacokinetic studies conducted in pregnant
patients.
Developmental toxicity studies were performed in rabbits (at oral
doses up to 1000 mg/kg/day) and rats (at oral doses up to 600
mg/kg/day). The reproductive toxicity study in rats was performed with
pre-, peri-, and postnatal evaluation. The highest doses in these
studies produced systemic exposures in these species approximately 3-
to 4-fold the exposure at the recommended human dose. In both rabbits
and rats, no treatment-related effects on embryonic/fetal survival or
fetal weights were observed. In addition, no treatment-related
external, visceral, or skeletal changes were observed in rabbits.
However, treatment-related increases over controls in the incidence of
supernumerary ribs were seen in rats at 600 mg/kg/day (exposures
3-fold the exposure at the recommended human dose).
Placenta transfer of drug was demonstrated in both rats and
rabbits. At a maternal dose of 600 mg/kg/day in rats, mean drug
concentrations in fetal plasma were approximately 1.5- to 2.5-fold
greater than in maternal plasma at 1 hour and 24 hours postdose,
respectively. Mean drug concentrations in fetal plasma were
approximately 2% of the mean maternal concentration at both 1 and 24
hours postdose at a maternal dose of 1000 mg/kg/day in rabbits.
Antiretroviral Pregnancy Registry
To monitor maternal-fetal outcomes of pregnant patients exposed to
ISENTRESS, an Antiretroviral Pregnancy Registry has been established.
Physicians are encouraged to register patients by calling
1-800-258-4263.
8.3 Nursing Mothers
Breast-feeding is not recommended while taking ISENTRESS. In
addition, it is recommended that HIV-infected mothers not breast-feed
their infants to avoid risking postnatal transmission of HIV.
It is not known whether raltegravir is secreted in human milk.
However, raltegravir is secreted in the milk of lactating rats. Mean
drug concentrations in milk were approximately 3-fold greater than
those in maternal plasma at a maternal dose of 600 mg/kg/day in rats.
There were no effects in rat offspring attributable to exposure of
ISENTRESS through the milk.
8.4 Pediatric Use
Safety and effectiveness of ISENTRESS in pediatric patients less
than 16 years of age have not been established.
8.5 Geriatric Use
Clinical studies of ISENTRESS did not include sufficient numbers
of subjects aged 65 and over to determine whether they respond
differently from younger subjects. Other reported clinical experience
has not identified differences in responses between the elderly and
younger subjects. In general, dose selection for an elderly patient
should be cautious, reflecting the greater frequency of decreased
hepatic, renal, or cardiac function, and of concomitant disease or
other drug therapy.
8.6 Use in Patients with Hepatic Impairment
No clinically important pharmacokinetic differences between
subjects with moderate hepatic impairment and healthy subjects were
observed. No dosage adjustment is necessary for patients with mild to
moderate hepatic impairment. The effect of severe hepatic impairment
on the pharmacokinetics of raltegravir has not been studied (see
Clinical Pharmacology (12.3)).
8.7 Use in Patients with Renal Impairment
No clinically important pharmacokinetic differences between
subjects with severe renal impairment and healthy subjects were
observed. No dosage adjustment is necessary (see Clinical Pharmacology
(12.3)).
10 OVERDOSAGE
No specific information is available on the treatment of
overdosage with ISENTRESS. Doses as high as 1600-mg single dose and
800-mg twice-daily multiple doses were studied in healthy volunteers
without evidence of toxicity. Occasional doses of up to 1800 mg per
day were taken in the P005/P018 & P019 studies without evidence of
toxicity.
In the event of an overdose, it is reasonable to employ the
standard supportive measures, e.g., remove unabsorbed material from
the gastrointestinal tract, employ clinical monitoring (including
obtaining an electrocardiogram), and institute supportive therapy if
required. The extent to which ISENTRESS may be dialyzable is unknown.
11 DESCRIPTION
ISENTRESS contains raltegravir potassium, a human immunodeficiency
virus integrase strand transfer inhibitor. The chemical name for
raltegravir potassium is
N-((4-Fluorophenyl)methyl)-1,6-dihydro-5-hydroxy-1-methyl-2-
(1-methyl-1-(((5-methyl-1,3,4-oxadiazol-2-yl)carbonyl)amino)ethyl)-6-
oxo-4-pyrimidinecarboxamide monopotassium salt.
The empirical formula is C20H20FKN6O5 and the molecular weight is
482.51. The structural formula is:
(OBJECT OMITTED)
Raltegravir potassium is a white to off-white powder. It is
soluble in water, slightly soluble in methanol, very slightly soluble
in ethanol and acetonitrile and insoluble in isopropanol.
Each film-coated tablet of ISENTRESS for oral administration
contains 434.4 mg of raltegravir potassium (as salt), equivalent to
400 mg of raltegravir (free phenol) and the following inactive
ingredients: microcrystalline cellulose, lactose monohydrate, calcium
phosphate dibasic anhydrous, hypromellose 2208, poloxamer 407
(contains 0.01% butylated hydroxytoluene as antioxidant), sodium
stearyl fumarate, magnesium stearate. In addition, the film coating
contains the following inactive ingredients: polyvinyl alcohol,
titanium dioxide, polyethylene glycol 3350, talc, red iron oxide and
black iron oxide.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Raltegravir is an HIV-1 antiviral drug (see Clinical Pharmacology
(12.4)).
12.2 Pharmacodynamics
In a monotherapy study raltegravir (400 mg twice daily)
demonstrated rapid antiviral activity with mean viral load reduction
of 1.66 log10 copies/mL by Day 10.
In Protocol 005 and Protocols 018 and 019, antiviral responses
were similar among subjects regardless of dose.
Effects on Electrocardiogram
In a randomized, placebo-controlled, crossover study, 31 healthy
subjects were administered a single oral supratherapeutic dose of
raltegravir 1600 mg and placebo. Peak raltegravir plasma
concentrations were approximately 4-fold higher than the peak
concentrations following a 400 mg dose. ISENTRESS did not appear to
prolong the QTc interval for 12 hours postdose. After baseline and
placebo adjustment, the maximum mean QTc change was -0.4 msec (1-sided
95% upper Cl: 3.1 msec).
12.3 Pharmacokinetics
Absorption
Raltegravir is absorbed with a Tmax of approximately 3 hours
postdose in the fasted state. Raltegravir AUC and Cmax increase dose
proportionally over the dose range 100 mg to 1600 mg. Raltegravir
C12hr increases dose proportionally over the dose range of 100 to 800
mg and increases slightly less than dose proportionally over the dose
range 100 mg to 1600 mg. With twice-daily dosing, pharmacokinetic
steady state is achieved within approximately the first 2 days of
dosing. There is little to no accumulation in AUC and Cmax. The
average accumulation ratio for C12hr ranged from approximately 1.2 to
1.6.
The absolute bioavailability of raltegravir has not been
established.
In subjects who received 400 mg twice daily alone, raltegravir
drug exposures were characterized by a geometric mean AUC0-12hr of
14.3 (mu)M-hr and C12hr of 142 nM.
Considerable variability was observed in the pharmacokinetics of
raltegravir. For observed C12hr in Protocols 018 and 019, the
coefficient of variation (CV) for inter-subject variability = 212% and
the CV for intra-subject variability = 122%.
Effect of Food on Oral Absorption
ISENTRESS may be administered without regard to food.
Administration of raltegravir following a high-fat meal increased
raltegravir AUC by approximately 19%. A high-fat meal slowed the rate
of absorption resulting in an approximately 34% decrease in Cmax, an
8.5-fold increase in C12hr, and a delay in Tmax following a single 400
mg dose. The effect of consumption of a range of food types on
steady-state pharmacokinetics is not known. Raltegravir was
administered without regard to food in the pivotal safety and efficacy
studies in HIV-1 positive subjects.
Distribution
Raltegravir is approximately 83% bound to human plasma protein
over the concentration range of 2 to 10 uM.
Metabolism and Excretion
The apparent terminal half-life of raltegravir is approximately 9
hours, with a shorter (alpha)-phase half-life (approximately 1 hour)
accounting for much of the AUC. Following administration of an oral
dose of radiolabeled raltegravir, approximately 51 and 32% of the dose
was excreted in feces and urine, respectively. In feces, only
raltegravir was present, most of which is likely derived from
hydrolysis of raltegravir-glucuronide secreted in bile as observed in
preclinical species. Two components, namely raltegravir and
raltegravir-glucuronide, were detected in urine and accounted for
approximately 9 and 23% of the dose, respectively. The major
circulating entity was raltegravir and represented approximately 70%
of the total radioactivity; the remaining radioactivity in plasma was
accounted for by raltegravir-glucuronide. Studies using
isoform-selective chemical inhibitors and cDNA-expressed
UDP-glucuronosyltransferases (UGT) show that UGT1A1 is the main enzyme
responsible for the formation of raltegravir-glucuronide. Thus, the
data indicate that the major mechanism of clearance of raltegravir in
humans is UGT1A1-mediated glucuronidation.
Special Populations
Pediatric
The pharmacokinetics of raltegravir in pediatric patients has not
been established.
Age
The effect of age on the pharmacokinetics of raltegravir was
evaluated in the composite analysis. No dosage adjustment is
necessary.
Race
The effect of race on the pharmacokinetics of raltegravir was
evaluated in the composite analysis. No dosage adjustment is
necessary.
Gender
A study of the pharmacokinetics of raltegravir was performed in
young healthy males and females. Additionally, the effect of gender
was evaluated in a composite analysis of pharmacokinetic data from 103
healthy subjects and 28 HIV-1 infected subjects receiving raltegravir
monotherapy with fasted administration. No dosage adjustment is
necessary.
Hepatic Impairment
Raltegravir is eliminated primarily by glucuronidation in the
liver. A study of the pharmacokinetics of raltegravir was performed in
subjects with moderate hepatic impairment. Additionally, hepatic
impairment was evaluated in the composite pharmacokinetic analysis.
There were no clinically important pharmacokinetic differences between
subjects with moderate hepatic impairment and healthy subjects. No
dosage adjustment is necessary for patients with mild to moderate
hepatic impairment. The effect of severe hepatic impairment on the
pharmacokinetics of raltegravir has not been studied.
Renal Impairment
Renal clearance of unchanged drug is a minor pathway of
elimination. A study of the pharmacokinetics of raltegravir was
performed in subjects with severe renal impairment. Additionally,
renal impairment was evaluated in the composite pharmacokinetic
analysis. There were no clinically important pharmacokinetic
differences between subjects with severe renal impairment and healthy
subjects. No dosage adjustment is necessary. Because the extent to
which ISENTRESS may be dialyzable is unknown, dosing before a dialysis
session should be avoided.
UGT1A1 Polymorphism
Data currently available are not sufficient to determine the
impact of UGT1A1 polymorphism on raltegravir pharmacokinetics.
Drug Interactions (see Drug Interactions (7)).
Table 4: Effect of Other Agents on the Pharmacokinetics of
Raltegravir
Ratio (90% Confidence
Interval) of Raltegravir
Pharmacokinetic
Parameters with/without
Coadministered Drug;
Coadministered No Effect = 1.00
Coadministered Drug Raltegravir -------------------------
Drug Dose/Schedule Dose/Schedule n Cmax
--------------- -------------- ------------- ------ ------------------
atazanavir 400 mg daily 100 mg single
dose 10 1.53 (1.11, 2.12)
--------------- -------------- ------------- ------ ------------------
atazanavir/ 300 mg/100 mg 400 mg twice
ritonavir daily daily 10 1.24 (0.87, 1.77)
--------------- -------------- ------------- ------ ------------------
efavirenz 600 mg daily 400 mg single
dose 9 0.64 (0.41, 0.98)
--------------- -------------- ------------- ------ ------------------
rifampin 600 mg daily 400 mg single
dose 9 0.62 (0.37, 1.04)
--------------- -------------- ------------- ------ ------------------
ritonavir 100 mg twice 400 mg single
daily dose 10 0.76 (0.55, 1.04)
--------------- -------------- ------------- ------ ------------------
tenofovir 300 mg daily 400 mg twice
daily 9 1.64 (1.16, 2.32)
--------------- -------------- ------------- ------ ------------------
tipranavir/ 500 mg/200 mg 400 mg twice 15
ritonavir twice daily daily (14
for
Cmin) 0.82 (0.46, 1.46)
--------------- -------------- ------------- ------ ------------------
Ratio (90% Confidence Interval) of
Raltegravir Pharmacokinetic
Parameters with/without
Coadministered Drug;
No Effect = 1.00
-------------------------------------
Coadministered Drug AUC Cmin
--------------------------------- ----------------- -----------------
atazanavir
1.72 (1.47, 2.02) 1.95 (1.30, 2.92)
--------------------------------- ----------------- -----------------
atazanavir/ ritonavir 1.41 (1.12, 1.78) 1.77 (1.39, 2.25)
--------------------------------- ----------------- -----------------
efavirenz 0.64 (0.52, 0.80) 0.79 (0.49, 1.28)
--------------------------------- ----------------- -----------------
rifampin 0.60
(0.39, 0.91) 0.39 (0.30, 0.51)
--------------------------------- ----------------- -----------------
ritonavir 0.99
(0.70,
0.84 (0.70, 1.01) 1.40)
--------------------------------- ----------------- -----------------
tenofovir 1.49 (1.15, 1.94) 1.03 (0.73, 1.45)
--------------------------------- ----------------- -----------------
tipranavir/ ritonavir 0.76 (0.49, 1.19) 0.45 (0.31, 0.66)
--------------------------------- ----------------- -----------------
12.4 Microbiology
Mechanism of Action
Raltegravir inhibits the catalytic activity of HIV-1 integrase, an
HIV-1 encoded enzyme that is required for viral replication.
Inhibition of integrase prevents the covalent insertion, or
integration, of unintegrated linear HIV-1 DNA into the host cell
genome preventing the formation of the HIV-1 provirus. The provirus is
required to direct the production of progeny virus, so inhibiting
integration prevents propagation of the viral infection. Raltegravir
did not significantly inhibit human phosphoryltransferases including
DNA polymerases (alpha), B, and (gamma).
Antiviral Activity in Cell Culture
Raltegravir at concentrations of 31 +/- 20 nM resulted in 95%
inhibition (EC95) of viral spread (relative to an untreated
virus-infected culture) in human T-lymphoid cell cultures infected
with the cell-line adapted HIV-1 variant H9IIIB. In addition,
raltegravir at concentrations of 6 to 50 nM resulted in 95% inhibition
of viral spread in cultures of mitogen-activated human peripheral
blood mononuclear cells infected with diverse, primary clinical
isolates of HIV-1, including isolates resistant to reverse
transcriptase inhibitors and protease inhibitors. Raltegravir also
inhibited replication of an HIV-2 isolate when tested in CEMx174 cells
(EC95 value = 6 nM). Additive to synergistic antiretroviral activity
was observed when human T-lymphoid cells infected with the H9IIIB
variant of HIV-1 were incubated with raltegravir in combination with
non-nucleoside reverse transcriptase inhibitors (delavirdine,
efavirenz, or nevirapine); nucleoside analog reverse transcriptase
inhibitors (abacavir, didanosine, lamivudine, stavudine, tenofovir,
zalcitabine, or zidovudine); protease inhibitors (amprenavir,
atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, or
saquinavir); or the entry inhibitor enfuvirtide.
Resistance
The mutations observed in the HIV-1 integrase coding sequence that
contributed to raltegravir resistance (evolved either in cell culture
or in subjects treated with raltegravir) generally included an amino
acid substitution at either Q148 (changed to H, K, or R) or N155
(changed to H) plus one or more additional substitutions (i.e.,
L74M/R, E92Q, T97A, E138A/K, G140A/S, V151I, G163R, H183P, Y226D/F/H,
S230R and D232N). Amino acid substitution at Y143C/H/R is another
pathway to raltegravir resistance.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term (2-year) carcinogenicity studies of raltegravir in
rodents are ongoing.
No evidence of mutagenicity or genotoxicity was observed in in
vitro microbial mutagenesis (Ames) tests, in vitro alkaline elution
assays for DNA breakage and in vitro and in vivo chromosomal
aberration studies.
No effect on fertility was seen in male and female rats at doses
up to 600 mg/kg/day which resulted in a 3-fold exposure above the
exposure at the recommended human dose.
14 CLINICAL STUDIES
Description of Clinical Studies
The evidence of efficacy of ISENTRESS is based on the analyses of
24-week data from 2 ongoing, randomized, double-blind,
placebo-controlled trials, BENCHMRK 1 and BENCHMRK 2 (Protocols 018
and 019), in antiretroviral treatment-experienced HIV-1 infected adult
subjects. These efficacy results were supported by the 48-week
analysis of a randomized, double-blind, controlled, dose-ranging
trial, Protocol 005, in antiretroviral treatment-experienced HIV-1
infected adult subjects.
Treatment-Experienced Subjects
BENCHMRK 1 and BENCHMRK 2 are Phase III studies to evaluate the
safety and antiretroviral activity of ISENTRESS 400 mg twice daily in
combination with an optimized background therapy (OBT), versus OBT
alone, in HIV-infected subjects, 16 years or older, with documented
resistance to at least 1 drug in each of 3 Classes (NNRTIs, NRTIs,
PIs) of antiretroviral therapies. Randomization was stratified by
degree of resistance to PI (1PI vs. >1PI) and the use of enfuvirtide
in the OBT. Prior to randomization, OBT was selected by the
investigator based on genotypic/phenotypic resistance testing and
prior ART history.
Table 5 shows the demographic characteristics of subjects in the
ISENTRESS 400 mg twice daily arm and subjects in the placebo arm.
Table 5: Baseline Characteristics
ISENTRESS
400 mg
Twice Daily Placebo
BENCHMRK 1 and 2 Pooled + OBT + OBT
(N = 462) (N = 237)
--------------------------------------------- ------------ ----------
Gender n (%)
--------------------------------------------- ------------ ----------
Male 405 (87.7) 210 (88.6)
Female 57 (12.3) 27 (11.4)
--------------------------------------------- ------------ ----------
Race n (%)
--------------------------------------------- ------------ ----------
White 301 (65.2) 173 (73.0)
Black 66 (14.3) 26 (11.0)
Asian 16 (3.5) 6 (2.5)
Hispanic 53 (11.5) 19 (8.0)
Others 26 (5.6) 13 (5.5)
--------------------------------------------- ------------ ----------
Age (years)
--------------------------------------------- ------------ ----------
Median (min, max) 45.0 (16 to 45.0 (17
74) to 70)
--------------------------------------------- ------------ ----------
CD4+ Cell Count
--------------------------------------------- ------------ ----------
Median (min, max), cells/mm3 119 (1 to 123 (0 to
792) 759)
=50 cells/mm3, n (%) 146 (31.6) 78 (32.9)
>50 and =200 cells/mm3, n (%) 173 (37.4) 85 (35.9)
--------------------------------------------- ------------ ----------
Plasma HIV-1 RNA
--------------------------------------------- ------------ ----------
Median (min, max), log10 copies/mL 4.8 (2 to 6) 4.7 (2 to
6)
>100,000 copies/mL, n (%) 164 (35.5) 78 (32.9)
--------------------------------------------- ------------ ----------
History of AIDS n (%)
--------------------------------------------- ------------ ----------
Yes 426 (92.2) 216 (91.1)
--------------------------------------------- ------------ ----------
Prior Use of ART, Median (1st Quartile, 3rd Quartile)
----------------------------------------------------------------------
Years of ART Use 10.1 (7.4 to 10.2 (7.9
12.1) to 12.4)
Number of ART 12.0 (9 to 12.0 (9 to
15) 14)
--------------------------------------------- ------------ ----------
Hepatitis Co-infection* n (%)
--------------------------------------------- ------------ ----------
No Hepatitis B or C virus 385 (83.3) 201 (84.8)
Hepatitis B virus only 36 (7.8) 7 (3.0)
Hepatitis C virus only 37 (8.0) 27 (11.4)
Co-infection of Hepatitis B and C virus 4 (0.9) 2 (0.8)
--------------------------------------------- ------------ ----------
Stratum n (%)
--------------------------------------------- ------------ ----------
Enfuvirtide in OBT 175 (37.9) 89 (37.6)
Resistant to =>2 PI 447 (96.8) 226 (95.4)
--------------------------------------------- ------------ ----------
*Hepatitis B virus surface antigen positive or hepatitis C virus
antibody positive.
Table 6 compares the characteristics of optimized background
therapy at baseline in the ISENTRESS 400 mg twice daily arm and
subjects in the control arm.
Table 6: Characteristics of Optimized Background Therapy at
Baseline
ISENTRESS
400 mg
Twice
Daily Placebo
BENCHMRK 1 and 2 Pooled + OBT + OBT
(N = 462) (N = 237)
------------------------------------------------ ---------- ----------
Number of ARTs in OBT
------------------------------------------------ ---------- ----------
Median (min, max) 4.0 (1 to 4.0 (2 to
7) 7)
------------------------------------------------ ---------- ----------
Number of Active PI in OBT by Phenotypic
Resistance Test*
------------------------------------------------ ---------- ----------
0 166 (35.9) 97 (40.9)
1 or more 278 (60.2) 137 (57.8)
------------------------------------------------ ---------- ----------
Phenotypic Sensitivity Score (PSS)+
------------------------------------------------ ---------- ----------
0 67 (14.5) 44 (18.6)
1 145 (31.4) 71 (30.0)
2 142 (30.7) 66 (27.8)
3 or more 85 (18.4) 48 (20.3)
------------------------------------------------ ---------- ----------
Genotypic Sensitivity Score (GSS)+
------------------------------------------------ ---------- ----------
0 115 (24.9) 65 (27.4)
1 178 (38.5) 96 (40.5)
2 111 (24.0) 49 (20.7)
3 or more 51 (11.0) 23 (9.7)
------------------------------------------------ ---------- ----------
* Darunavir use in OBT in darunavir naive subjects was counted as one
active PI.
+ The Phenotypic Sensitivity Score (PSS) and the Genotypic Sensitivity
Score (GSS) were defined as the total oral ARTs in OBT to which a
subject's viral isolate showed phenotypic sensitivity and genotypic
sensitivity, respectively, based upon phenotypic and genotypic
resistance tests. Enfuvirtide use in OBT in enfuvirtide-naive
subjects was counted as one active drug in OBT in the GSS and PSS.
Similarly, darunavir use in OBT in darunavir-naive subjects was
counted as one active drug in OBT.
Week 24 outcomes for subjects on the recommended dose of ISENTRESS
400 mg twice daily from the pooled studies BENCHMRK 1 and 2 are shown
in Table 7. The efficacy responses were evaluated based upon the 436
subjects from the pooled studies BENCHMRK 1 and 2 who had completed 24
weeks of treatment or discontinued earlier. All other outcomes were
based upon the total 699 subjects who were randomized and treated.
Table 7: Outcomes by Treatment Group through Week 24
ISENTRESS
400 mg
Twice
Daily Placebo
BENCHMRK 1 and 2 Pooled + OBT + OBT
n (%) (N = 462) (N = 237)
------------------------------------------------ ---------- ----------
Outcome at Week 24 n (%) n (%)
------------------------------------------------ ---------- ----------
Subjects with Week 24 data 286 150
Subjects with HIV-1 RNA less than 400 copies/mL* 216 (75.5) 59 (39.3)
Subjects with HIV-1 RNA less than 50 copies/mL* 179 (62.6) 50 (33.3)
------------------------------------------------ ---------- ----------
Virologic Failure (confirmed)+,++ 74 (16.0) 121 (51.1)
Non-responder+,++ 13 (2.8) 78 (32.9)
Rebound+,++ 61 (13.2) 43 (18.1)
------------------------------------------------ ---------- ----------
Death++,ss. 6 (1.3) 3 (1.3)
Discontinuation due to adverse experiences++,ss. 9 (1.9) 5 (2.1)
Discontinuation due to other reasons++,ss.,(A) 6 (1.3) 1 (0.4)
------------------------------------------------ ---------- ----------
*Based upon the 436 subjects with Week 24 data
+Virologic failure: defined as non-responders who did not achieve >1.0
log10 HIV-1 RNA reduction and 400 HIV-1 RNA copies/mL by Week 16, or
viral rebound, which was defined as: (a) HIV-1 RNA >400 copies/mL (on
2 consecutive measurements at least 1 week apart) after initial
response with HIV-1 RNA 400 copies/mL, or (b) >1.0 log10 increase in
HIV-1 RNA above nadir level (on 2 consecutive measurements at least 1
week apart).
++Based upon the total 699 subjects randomized and treated, not all
subjects complete to Week 24
ss.Includes available data beyond Week 24
(A) Includes loss to follow-up, subjects withdrew consent,
noncompliance, protocol violation and other reasons.
The mean changes in plasma HIV-1 RNA from baseline were -1.85
log10 copies/mL in the ISENTRESS 400 mg twice daily arm and -0.84
log10 copies/mL for the control arm. The mean increase from baseline
in CD4+ cell counts was higher in the arm receiving ISENTRESS 400 mg
twice daily (89 cells/mm(3)) than in the control arm (35 cells/mm(3)).
Virologic responses at Week 24 by baseline genotypic and
phenotypic sensitivity score are shown in Table 8.
Table 8: Virologic Response at Week 24 by Baseline
Genotypic/Phenotypic Sensitivity Score
BENCHMRK 1 and 2 Pooled Percent with HIV RNA
400 copies/mL
at Week 24
(Noncompleters as failures approach) -------------------------
ISENTRESS Placebo
400 mg + OBT
Twice (N =
Daily 150)
+ OBT
n (N = 286) n
-------------------------------------------- --- --------- -- --------
Phenotypic Sensitivity Score (PSS)
*
-------------------------------------------- -------------------------
0 44 50 26 4
1 89 75 50 34
2 95 86 36 42
3 or more 48 73 33 67
Genotypic Sensitivity Score (GSS)*
-------------------------------------------- -------------------------
0 69 54 40 8
1 115 82 64 36
2 67 88 27 78
3 or more 30 70 18 61
-------------------------------------------- --- --------- -- --------
* The Phenotypic Sensitivity Score (PSS) and the Genotypic Sensitivity
Score (GSS) were defined as the total oral ARTs in OBT to which a
subject's viral isolate showed phenotypic sensitivity and genotypic
sensitivity, respectively, based upon phenotypic and genotypic
resistance tests. Enfuvirtide use in OBT in enfuvirtide-naive
subjects was counted as one active drug in OBT in the GSS and PSS.
Similarly, darunavir use in OBT in darunavir-naive subjects was
counted as one active drug in OBT.
BENCHMRK 1 and 2 Pooled Percent with HIV RNA
50 copies/mL
at Week 24
(Noncompleters as failures approach) ------------------------
ISENTRESS Placebo
400 mg + OBT
Twice (N =
Daily 150)
+ OBT
n (N = 286) n
-------------------------------------------- --- --------- -- -------
Phenotypic Sensitivity Score (PSS)
*
----------------------------------------------------------------------
0 44 41 26 4
1 89 66 50 30
2 95 70 36 36
3 or more 48 56 33 55
-------
Genotypic Sensitivity Score (GSS)*
----------------------------------------------------------------------
0 69 41 40 5
1 115 70 64 33
2 67 75 27 63
3 or more 30 53 18 50
-------------------------------------------- --- --------- -- -------
* The Phenotypic Sensitivity Score (PSS) and the Genotypic Sensitivity
Score (GSS) were defined as the total oral ARTs in OBT to which a
subject's viral isolate showed phenotypic sensitivity and genotypic
sensitivity, respectively, based upon phenotypic and genotypic
resistance tests. Enfuvirtide use in OBT in enfuvirtide-naive
subjects was counted as one active drug in OBT in the GSS and PSS.
Similarly, darunavir use in OBT in darunavir-naive subjects was
counted as one active drug in OBT.
16 HOW SUPPLIED/STORAGE AND HANDLING
ISENTRESS tablets 400 mg are pink, oval-shaped, film-coated
tablets with "227" on one side. They are supplied as follows:
NDC 0006-0227-61 unit-of-use bottles of 60.
No. 3894
Storage and Handling
Store at 20-25(degree)C (68-77(degree)F); excursions permitted to
15-30(degree)C (59-86(degree)F). See USP Controlled Room Temperature.
17 PATIENT COUNSELING INFORMATION
(See FDA-Approved Patient Labeling).
Patients should be informed that ISENTRESS is not a cure for HIV
infection or AIDS. They should also be told that people taking
ISENTRESS may still get infections or other conditions common in
people with HIV (opportunistic infections). In addition, patients
should be told that the long-term effects of ISENTRESS are not known
at this time. Patients should also be told that it is very important
that they stay under a physician's care during treatment with
ISENTRESS.
Patients should be informed that ISENTRESS does not reduce the
chance of passing HIV to others through sexual contact, sharing
needles, or being exposed to blood. Patients should be advised to
continue to practice safer sex and to use latex or polyurethane
condoms or other barrier methods to lower the chance of sexual contact
with any body fluids such as semen, vaginal secretions or blood.
Patients should also be advised to never re-use or share needles.
Physicians should instruct their patients that if they miss a
dose, they should take it as soon as they remember. If they do not
remember until it is time for the next dose, they should be instructed
to skip the missed dose and go back to the regular schedule. Patients
should not take two tablets of ISENTRESS at the same time.
Physicians should instruct their patients to read the Patient
Package Insert before starting ISENTRESS therapy and to reread each
time the prescription is renewed. Patients should be instructed to
inform their physician or pharmacist if they develop any unusual
symptom, or if any known symptom persists or worsens.
Manufactured and Distributed by:
MERCK & CO., INC., Whitehouse Station, NJ 08889, USA
Printed in USA
9795100
U.S. Patent Nos. US 7,169,780
(1) Trademark of MERCK & CO., Inc.
COPYRIGHT (C) 2007 MERCK & CO., Inc.
All rights reserved
Patient Information
ISENTRESS(TM) (eye sen tris)
(raltegravir)
Tablets
Read the patient information that comes with ISENTRESS(1) before
you start taking it and each time you get a refill. There may be new
information. This leaflet is a summary of the information for
patients. Your doctor or pharmacist can give you additional
information. This leaflet does not take the place of talking with your
doctor about your medical condition or your treatment.
What is ISENTRESS?
-- ISENTRESS is an anti-HIV (antiretroviral) medicine that helps
to control HIV infection. The term HIV stands for Human
Immunodeficiency Virus. It is the virus that causes AIDS
(Acquired Immune Deficiency Syndrome). ISENTRESS is used along
with other anti-HIV medicines in patients who are already
taking or have taken anti-HIV medicines and the medicines are
not controlling their HIV infection. ISENTRESS will NOT cure
HIV infection.
-- People taking ISENTRESS may still develop infections,
including opportunistic infections or other conditions that
happen with HIV infection.
-- Stay under the care of your doctor during treatment with
ISENTRESS.
-- The long-term effects of ISENTRESS are not known at this time.
-- The safety and effectiveness of ISENTRESS in children less
than 16 years of age has not been studied.
ISENTRESS must be used with other anti-HIV medicines.
How does ISENTRESS work?
-- ISENTRESS blocks an enzyme which the virus (HIV) needs in
order to make more virus. The enzyme that ISENTRESS blocks is
called HIV integrase.
-- When used with other anti-HIV medicines, ISENTRESS may do two
things:
1. It may reduce the amount of HIV in your blood. This is
called your "viral load".
2. It may also increase the number of white blood cells called
CD4 (T) cells that help fight off other infections.
-- ISENTRESS may not have these effects in all patients.
Does ISENTRESS lower the chance of passing HIV to other people?
No. ISENTRESS does not reduce the chance of passing HIV to others
through sexual contact, sharing needles, or being exposed to your
blood.
-- Continue to practice safer sex.
-- Use latex or polyurethane condoms or other barrier methods to
lower the chance of sexual contact with any body fluids. This
includes semen from a man, vaginal secretions from a woman, or
blood.
-- Never re-use or share needles.
Ask your doctor if you have any questions about safer sex or how
to prevent passing HIV to other people.
What should I tell my doctor before and during treatment with
ISENTRESS?
Tell your doctor about all of your medical conditions. Include any
of the following that applies to you:
-- You have any allergies.
-- You are pregnant or plan to become pregnant.
- ISENTRESS is not recommended for use during pregnancy.
ISENTRESS has not been studied in pregnant women. If you
take ISENTRESS while you are pregnant, talk to your doctor
about how you can be included in the Antiretroviral
Pregnancy Registry.
-- You are breast-feeding or plan to breast-feed.
- It is recommended that HIV-infected women should not
breast-feed their infants. This is because their babies could
be infected with HIV through their breast milk.
- Talk with your doctor about the best way to feed your baby.
Tell your doctor about all the medicines you take. Include the
following:
-- prescription medicines
-- non-prescription medicines
-- vitamins
-- herbal supplements
Know the medicines you take.
-- Keep a list of your medicines. Show the list to your doctor
and pharmacist when you get a new medicine.
How should I take ISENTRESS?
Take ISENTRESS exactly as your doctor has prescribed. The
recommended dose is as follows:
-- Take only one 400 mg tablet at a time.
-- Take it twice a day.
-- Take it by mouth.
-- Take it with or without food.
Do not change your dose or stop taking ISENTRESS or your other
anti-HIV medicines without first talking with your doctor.
IMPORTANT: Take ISENTRESS exactly as your doctor prescribed and at
the right times of day because if you don't:
-- The amount of virus (HIV) in your blood may increase if the
medicine is stopped for even a short period of time.
-- The virus may develop resistance to ISENTRESS and become
harder to treat.
-- Your medicines may stop working to fight HIV.
-- The activity of ISENTRESS may be reduced (due to resistance).
If you fail to take ISENTRESS the way you should, here's what to
do:
-- If you miss a dose, take it as soon as you remember. If you do
not remember until it is time for your next dose, skip the
missed dose and go back to your regular schedule. Do NOT take
two tablets of ISENTRESS at the same time. In other words, do
NOT take a double dose.
-- If you take too much ISENTRESS, call your doctor or local
Poison Control Center.
Be sure to keep a supply of your anti-HIV medicines.
-- When your ISENTRESS supply starts to run low, get more from
your doctor or pharmacy.
-- Do not wait until your medicine runs out to get more.
What are the possible side effects of ISENTRESS?
When ISENTRESS has been given with other anti-HIV drugs, the most
common side effects included:
-- diarrhea
-- nausea
-- headache
A condition called Immune Reconstitution Syndrome can happen in
some patients with advanced HIV infection (AIDS) when combination
antiretroviral treatment is started. Signs and symptoms of
inflammation from opportunistic infections that a person has or had
may occur as the medicines work to control the HIV infection and
strengthen the immune system. Call your doctor right away if you
notice any signs or symptoms of an infection after starting ISENTRESS
with other anti-HIV medicines.
Contact your doctor promptly if you experience unexplained muscle
pain, tenderness, or weakness while taking ISENTRESS.
Tell your doctor if you have any side effect that bothers you or
that does not go away.
These are not all the side effects of ISENTRESS. For more
information, ask your doctor or pharmacist.
How should I store ISENTRESS?
-- Store ISENTRESS at room temperature (68 to 77-degree F).
-- Keep ISENTRESS and all medicines out of the reach of children.
General information about the use of ISENTRESS
Medicines are sometimes prescribed for conditions that are not
mentioned in patient information leaflets.
-- Do not use ISENTRESS for a condition for which it was not
prescribed.
-- Do not give ISENTRESS to other people, even if they have the
same symptoms you have. It may harm them.
This leaflet gives you the most important information about
ISENTRESS.
-- If you would like to know more, talk with your doctor.
-- You can ask your doctor or pharmacist for additional
information about ISENTRESS that is written for health
professionals.
-- For more information go to www.ISENTRESS.com or call
1-800-622-4477.
What are the ingredients in ISENTRESS?
Active ingredient: Each film-coated tablet contains 400 mg of
raltegravir.
Inactive ingredients: Microcrystalline cellulose, lactose
monohydrate, calcium phosphate dibasic anhydrous, hypromellose 2208,
poloxamer 407 (contains 0.01% butylated hydroxytoluene as
antioxidant), sodium stearyl fumarate, magnesium stearate. In
addition, the film coating contains the following inactive
ingredients: polyvinyl alcohol, titanium dioxide, polyethylene glycol
3350, talc, red iron oxide and black iron oxide.
Manufactured and Distributed by:
MERCK & CO., Inc.
Whitehouse Station, NJ 08889, USA
Revised October 2007
9795100
U.S. Patent Nos. US 7,169,780
(1) Trademark of MERCK & CO., Inc. COPYRIGHT (C) 2007 MERCK & CO.,
Inc. All rights reserved
